ERC FUNDED PROJECTS

Despite more than fifty years of scientific progress since Richard Feynman's 1959 vision for nanotechnology, there is only one way to manipulate individual atoms in materials: scanning tunneling microscopy. Since the late 1980s, its atomically sharp tip has been used to move atoms over clean metal surfaces held at cryogenic temperatures. Scanning transmission electron microscopy, on the other hand, has been able to resolve atoms only more recently by focusing the electron beam with sub-atomic precision. This is especially useful in the two-dimensional form of hexagonally bonded carbon called graphene, which has superb electronic and mechanical properties. Several ways to further engineer those have been proposed, including by doping the structure with substitutional heteroatoms such as boron, nitrogen, phosphorus and silicon. My recent discovery that the scattering of the energetic imaging electrons can cause a silicon impurity to move through the graphene lattice has revealed a potential for atomically precise manipulation using the Ångström-sized electron probe. To develop this into a practical technique, improvements in the description of beam-induced displacements, advances in heteroatom implantation, and a concerted effort towards the automation of manipulations are required. My project tackles these in a multidisciplinary effort combining innovative computational techniques with pioneering experiments in an instrument where a low-energy ion implantation chamber is directly connected to an advanced electron microscope. To demonstrate the power of the method, I will prototype an atomic memory with an unprecedented memory density, and create heteroatom quantum corrals optimized for their plasmonic properties. The capability for atom-scale engineering of covalent materials opens a new vista for nanotechnology, pushing back the boundaries of the possible and allowing a plethora of materials science questions to be studied at the ultimate level of control.

1 497 202 €

Start date: 2017-10-01, End date: 2022-09-30

The goal of this proposal is to deliver a new theoretical framework to understand how transcription factors (TFs) sustain cell identity during developmental processes. Recognised as key drivers of cell fate acquisition, TFs are currently not considered to directly contribute to the mitotic inheritance of chromatin states. Instead, these are passively propagated through cell division by a variety of epigenetic marks. Recent discoveries, including by our lab, challenge this view: developmental TFs may impact the propagation of regulatory information from mother to daughter cells through a process known as mitotic bookmarking. This hypothesis, largely overlooked by mainstream epigenetic research during the last two decades, will be investigated in embryo-derived stem cells and during early mouse development. Indeed, these immature cell identities are largely independent from canonical epigenetic repression; hence, current models cannot account for their properties. We will comprehensively identify mitotic bookmarking factors in stem cells and early embryos, establish their function in stem cell self-renewal, cell fate acquisition and dissect how they contribute to chromatin regulation in mitosis. This will allow us to study the relationships between bookmarking factors and other mechanisms of epigenetic inheritance. To achieve this, unique techniques to modulate protein activity and histone modifications specifically in mitotic cells will be established. Thus, a mechanistic understanding of how mitosis influences gene regulation and of how mitotic bookmarking contributes to the propagation of immature cell identities will be delivered. Based on robust preliminary data, we anticipate the discovery of new functions for TFs in several genetic and epigenetic processes. This knowledge should have a wide impact on chromatin biology and cell fate studies as well as in other fields studying processes dominated by TFs and cell proliferation.

1 900 844 €

Start date: 2018-09-01, End date: 2023-08-31

Epigenetics research has revealed that in the cell’s nucleus all kinds of biomolecules–DNA, RNAs, proteins, protein posttranslational modifications–are highly compartmentalized to occupy distinct chromatin territories and genomic loci, thereby contributing to gene regulation and cell identity. In contrast, small molecules and cellular metabolites are generally considered to passively enter the nucleus from the cytoplasm and to lack distinct subnuclear localization. The CHROMABOLISM proposal challenges this assumption based on preliminary data generated in my laboratory. I hypothesize that chromatin-bound enzymes of central metabolism and subnuclear metabolite gradients contribute to gene regulation and cellular identity. To address this hypothesis, we will first systematically profile chromatin-bound metabolic enzymes, chart nuclear metabolomes across representative leukemia cell lines, and develop tools to measure local metabolite concentrations at distinct genomic loci. In a second step, we will then develop and apply technology to perturb these nuclear metabolite patterns by forcing the export of metabolic enzymes for the nucleus, aberrantly recruiting these enzymes to selected genomic loci, and perturbing metabolite patterns by addition and depletion of metabolites. In all these conditions we will measure the impact of nuclear metabolism on chromatin structure and gene expression. Based on the data obtained, we will model for the effects of cellular metabolites on cancer cell identity and proliferation. In line with the recent discovery of oncometabolites and the clinical use of antimetabolites, we expect to predict chromatin-bound metabolic enzymes that can be exploited as druggable targets in oncology. In a final aim we will validate these targets in leukemia and develop chemical probes against them. Successful completion of this project has the potential to transform our understanding of nuclear metabolism in control of gene expression and cellular identity.

1 980 916 €

Start date: 2018-05-01, End date: 2023-04-30

Developing tissues have a remarkable plasticity illustrated by their capacity to regenerate and form normal organs despite strong perturbations. This requires the adjustment of single cell behaviour to their neighbours and to tissue scale parameters. The modulation of cell growth and proliferation was suggested to be driven by mechanical inputs, however the mechanisms adjusting cell death are not well known. Recently it was shown that epithelial cells could be eliminated by spontaneous live-cell delamination following an increase of cell density. Studying cell delamination in the midline region of the Drosophila pupal notum, we confirmed that local tissue crowding is necessary and sufficient to drive cell elimination and found that Caspase 3 activation precedes and is required for cell delamination. This suggested that a yet unknown pathway is responsible for crowding sensing and activation of caspase, which does not involve already known mechanical sensing pathways. Moreover, we showed that fast growing clones in the notum could induce neighbouring cell elimination through crowding-induced death. This suggested that crowding-induced death could promote tissue invasion by pretumoural cells. Here we will combine genetics, quantitative live imaging, statistics, laser perturbations and modelling to study crowding-induced death in Drosophila in order to: 1) find single cell deformations responsible for caspase activation; 2) find new pathways responsible for density sensing and apoptosis induction; 3) test their contribution to adult tissue homeostasis, morphogenesis and cell elimination coordination; 4) study the role of crowding induced death during competition between different cell types and tissue invasion 5) Explore theoretically the conditions required for efficient space competition between two cell populations. This project will provide essential information for the understanding of epithelial homeostasis, mechanotransduction and tissue invasion by tumoural cells

1 489 147 €

Start date: 2018-01-01, End date: 2022-12-31

Over the last years, the landscape of the organic chemistry has been reshaped with impressive advances made in the transition metal-catalyzed carbon-hydrogen (C-H) bond functionalization field. Indeed, the functionalization of building blocks that do not display a reactive functional group but only a simple C-H bond is attractive as it avoids time-consuming and expensive prefunctionalization steps and limits the generation of waste. However, as energies required to break C-H bonds are similar, the differentiation between two C-H bonds and the selective functionalization of only one of them remain a key challenge. Therefore, the available approaches are still unsatisfactory due to important limitations: low reactivity, limited scopes and selectivity issues. In this proposal, a general approach to functionalize a CH bond located at a Far position (from a functional group) by Catalysis (FarCatCH) will be implemented with a special focus on underexplored transformations, affording important sulfur-and fluorine-containing compounds. Herein, I will develop new synthetic approaches for the remote functionalization of molecules based on i) a substrate-selectivity control and ii) the design of new catalysts using supramolecular tools. I will then iii) address a longstanding reactivity issue in organic synthesis: the trifluoromethylation of aliphatic compounds and apply the supramolecular catalysts for a remote enantioselective transformation. Designing a full set of tools as Swiss army knife for the selective functionalization at unconventional positions inaccessible so far, can considerably change the way organic molecules are made. These original technologies will offer new synthetic routes to access original sulfur- and fluorine-containing molecules, compounds of interest in drugs discovery, material sciences, pharmaceutical and agrochemical industry.

1 497 996 €

Start date: 2018-01-01, End date: 2022-12-31

The dynamics of weakly-coupled quantum matter can be solved by techniques deriving from perturbative quantum field theory. Conventional metals are described by long-lived quasiparticles (Fermi liquids). No such methods are available for strongly-coupled quantum matter where quasiparticles are short-lived, like the Quark-Gluon-Plasma, high Tc superconductors (HTCs) or graphene near the charge neutrality point. In HTCs, it has been argued the interaction timescale is the fastest scale in the system, which warrants a hydrodynamic description. In a recent series of remarkable theoretical and experimental developments, hyrodynamics signatures have been discovered in several strongly-coupled quantum systems such as graphene, delafossites and HTCs. Further theoretical progress is impeded by the lack of symmetry: momentum is only approximately conserved, which complicates the use of hydrodynamics as an effective low-energy theory; and the strange metallic phenomenology of HTCs, believed to originate from a quantum critical point, is not captured by conventional scaling arguments. New ideas are required to move beyond the current state of the art. Gauge/Gravity duality is a radically new approach which links a relativistic strongly-coupled quantum field theory to a classical theory of gravity. The hydrodynamic regime of the QGP has been very successfully described by these methods, which predict a shear viscosity very close to experimental values. Our focus in this proposal is to use holography to consistently model hydrodynamics with momentum relaxation and study its interplay with unconventional quantum criticality. This is crucial for a better understanding of the phenomenology in strongly-coupled quantum matter. As many systems are not relativistic, we will also consider hydrodynamics in non-relativistic holographic theories, thus enhancing our understanding of holographic dualities beyond the original Anti de Sitter/Conformal Field Theory correspondence.

1 498 028 €

Start date: 2018-09-01, End date: 2023-08-31

This “Life-Cycle” ERC proposal aims to develop a new class of artificial supramolecular materials that are kept in sustained non-equilibrium states by continuous dissipation of chemical fuels. Supramolecular polymers in current artificial materials stick together through weak reversible bonds that can be exchange by thermal energy. In contrast, natural supramolecular polymers such as those in the cytoskeletal network use chemical fuels such as adenosine triphosphate (ATP) to achieve an incredible adaptivity, motility, growth, and response to external inputs. Development of chemically fueled artificial supramolecular polymers should therefore lead to more life-like materials that could perform functions so far reserved only for living beings. The proposed materials are based on supramolecular reaction cycles that have both positive and negative feedback in order to achieve emergent properties, such as oscillations and waves. Two different approaches are used: i) supramolecular polymers that are fueled by redox reactions, and ii) enzyme-switchable supramolecular polymers that consume one of the natural fuels, namely ATP. The proposed polymers self-assemble cooperatively, which is used as a positive feedback mechanism. Using other co-assembling species we can engineer negative feedback in our reaction cycles to obtain unique supramolecular dynamics. Since the building blocks react, but also self-assemble they have built-in chemomechanical properties, much like in living materials such as the cytoskeleton. First we study the temporal behavior (part A) of our reaction cycles in well-stirred environments. Next, we move to non-stirred conditions (part B), where spatiotemporal behavior can be studied. And lastly, we develop free-standing non-equilibrium interactive materials based on our reaction cycles (part C). Overall, our approach opens a new way to obtain more life-like artificial materials that can eventually perform complex (biological) functions.

1 762 488 €

Start date: 2018-01-01, End date: 2022-12-31

A fundamental difference between man-made and living matter is metabolism: the ability to dissipate chemical energy to drive many different chemical processes out of equilibrium. Metabolism endows chemical systems within living organisms with properties that are standard in biology but odd in chemistry: the capability to process information, to move and to react to the external world. My goal is to endow soft materials with dynamic life-like properties. I have chosen four: molecular computation, movement, self-construction and the capacity to entertain complex chemical conversations with living cells. To do so I will embed stimuli-responsive materials with a biocompatible synthetic metabolism capable of sustaining autonomous chemical feedback loops that process information and perform autonomous macroscopic actions. My approach combines concepts from systems chemistry, synthetic biology and DNA molecular programming with soft materials and uses a biochemical system that I have contributed to pioneer: DNA/enzyme active solutions that remain out of equilibrium by consuming a chemical fuel with non-trivial reaction kinetics. This system has three unique properties: programmability, biocompatibility and a long-term metabolic autonomy. Metabolic matter will be assembled in two stages: i) enabling metabolic materials with dynamic chemical, biological and mechanical responses, and ii) creating metabolic materials with unprecedented properties, in particular, the capacity of self-construction, which I will seek by emulating embryogenesis, and the ability to autonomously pattern a community of living cells. By doing this I will create for the first time chemical matter that is both dynamically and structurally complex, thus bringing into the realm of synthetic chemistry behaviors that so far only existed in biological systems. In the long term, metabolic matter could provide revolutionary solutions for soft robotics and tissue engineering.

1 899 333 €

Start date: 2018-06-01, End date: 2023-05-31

Oxygen is an element of major importance, due to its presence in the vast majority of molecules and materials. Over the years, much effort has been put into the development of analytical techniques allowing the study of oxygen environments, in view of elucidating key questions about the structure and reactivity of a variety of systems. In this context, Nuclear Magnetic Resonance (NMR) spectroscopy has been the focus of much attention, because it has progressively emerged as a technique capable of providing deep insight into the local structure around this atom. However, NMR spectroscopy is highly challenging for oxygen, mainly because the NMR-active isotope, oxygen-17, has a very low natural abundance (0.04%), and hence a very poor sensitivity. Because of this, the majority of 17O NMR studies require enriching the molecules and materials of interest in 17O. Unfortunately, 17O-labelling is simply unaffordable at the moment for most research groups, meaning that 17O NMR spectroscopy is inaccessible to the broad community, and still considered as an “exotic” tool of analysis. In this ERC project, the goal is to develop new rapid, user-friendly, and low-cost protocols for enriching a wide variety of organic and inorganic compounds in 17O by using mechanosynthesis. This original approach will then be taken as a unique opportunity (i) to push the current boundaries of 17O solid state NMR spectroscopy (by developing new tools for studying the structure of complex molecular and materials systems), and (ii) to elucidate major questions which could not be addressed so far, especially concerning reaction mechanisms between solids and the structure of interfaces of biological relevance. In doing so, the overall idea is to make 17O NMR spectroscopy become a more standard analytical tool used by a vast research community, including chemists, biologists and physicists.

1 999 836 €

Start date: 2018-10-01, End date: 2023-09-30